Prevalent, morbid, and costly ($20 billion/year in 2000), urinary incontinence is a major problem, especially for older adults in whom the most common type is urge incontinence (UUI). Generally ascribed to bladder spasms, UUI's actual causes are unknown, and therapy remains inadequate and little improved over the last 50 years. Recent evidence suggests that one of its causes is poor bladder control by the brain. In our current R01 we have used a recommended treatment - biofeedback (BFB) - as a probe to explore this. The goal of the proposed new study is to build on this knowledge by using a drug probe with a different mode of action. Data suggest that bladder control comprises 3 cerebral circuits, which help to maintain continence by suppressing the voiding reflex located in the midbrain. One circuit involves the medial prefrontal cortex (mPFC) and another midcingulate cortex (which includes dorsal anterior cingulate cortex and supplemental motor area); the insula is also implicated. BFB, which focuses on strengthening voluntary control of the bladder, seems to improve incontinence by enhancing deactivation of the first brain circuit and thereby resulting in less activation of the second; it has no effect on the insula. Yet, BFB is used far less than drugs to treat UUI. Mechanism(s) mediating drug response are unknown but likely involve afferent activity ascending to the brain. The proposed study would be the first to address this critical knowledge gap. It is based on hypotheses generated from our BFB study, as well as a pilot study of the bladder relaxant fesoterodine and the working model of CNS/bladder control. Specific aims are to determine: (1) whether different regional patterns of brain activation/deactivation in the midcingulate cortex or mPFC-or the insula, given the perceived impact of antimuscarinics on afferents-predict response or non-response to treatment (as for BFB); (2) whether successful treatment of incontinence reduces activation of the midcingulate cortex, confirming that its activation is compensatory rather than causal; and (3) whether improvement of incontinence is mediated by changes in mPFC deactivation, suggesting improved conscious control. To address these aims, we will randomize 152 women aged e60 years to receive 12 weeks of either fesoter- odine or placebo and then to be switched to the alternate therapy for another 12 weeks. The study will enable us to correlate the change in CNS activation/deactivation with clinical response to therapy and also to discern whether CNS changes revert as incontinence worsens following withdrawal of therapy (on placebo). Regardless of the results, knowledge from this study will contribute substantially to current understanding of the cause(s) of UUI and to the mechanisms that underlie/mediate its successful treatment. Such knowledge may also allow differentiation of different types of UUI and facilitate development of more effective therapy.